Delta-17 and delta-20 olefinic and saturated 17β-substituted-4-aza-5α-androstan-3-ones as 5α-reductase inhibitors useful in the prevention and treatment of hyperandrogenic disorders

Abstract

Described are new delta-17 and delta-20 olefic and saturated 17 beta -substituted 4-aza-5 alpha -androstan-3-ones and related compounds and the use of such compounds as 5 alpha -reductase inhibitors for treatment of benign prostatic hyperplasia and other hyperandrogenic related disorders.

What is claimed is: 
     
       1. A compound of the formula: ##STR34## wherein: Alk is C 1  -C 4  straight or branched chain alkyl or alkenyl; dashed lines a, e and f each can independently represent a double bond when present, with the proviso that double bonds formed by e and f are not both present concurrently; R is hydrogen, methyl or ethyl;   R 2  is (b) COR 11  wherein R 11  is C 6  -C 10  aryl, or substituted C 6  -C 10  aryl;     (c) CONHR 12 , where R 12  is substituted phenyl; providing that in (b), or (c), Alk is alkenyl; wherein C 6  -C 10  aryl is selected from phenyl and naphthyl;   wherein said substituted aryl groups are substituted with a substituent selected from:     hydrogen;   C 1-8  straight or branched alkyl:   C 2-8  straight or branched alkenyl:   C 3-8  cycloalkyl:   C 2-8  alkynyl:   --CONR 4  R 5  where R 4  and R 5  independently are H, C 1-8  alkyl, C 3-8  cycloalkyl, C 1-4  perhaloalkyl, or phenyl;   --COR 4  ;   S(O) n  R 4  where n=0-2:   --OCOR 4  ;   --NR 4  (CO)NHR 5  ;   --NR 4  R 5  ;   CN   NO 2  ;   halo:   perhalo C 1  -C 4  alkyl;   --CO 2  R 4  ;   phenyl; and pharmaceutically acceptable salts thereof.     
     
     
       2. A compound of claim 1 wherein said aryl radical is phenyl. 
     
     
       3. A compound of claim 1 wherein said substituents are selected from: hydrogen; C 1-8  straight or branched alkyl;   --CONR 4  R 5  where R 4  and R 5  independently are H, C 1-8  alkyl, C 1-4  perhaloalkyl;   --COR 4  ;   --OCOR 4  ;   --NR 4  (CO)R 5  ;   --NR 4  (CO)NHR 5  ;   --NHSO 2  R 4  ;   --OR 4  ;   --NR 4  R 5  ;   CN;   NO 2  ;   halo;   perhalo C 1  -C 4  alkyl;   --CO 2  R 4 .   
     
     
       4. A compound of claim 1 of the formula: ##STR35## wherein the dashed line a represents a double bond when present, R and R 1  are selected from hydrogen, methyl and ethyl; and R 2  is as defined in claim 1, including both (E) and (Z) forms, and mixtures thereof.   
     
     
       5. A compound of claim 4 where R 1  is methyl. 
     
     
       6. A compound of claim 4 where R 1  is hydrogen. 
     
     
       7. A compound of selected from: 4-methyl-24-nor-4-aza-5α-cholane-23-nitrile,   (20R)-4-methyl-3-oxo-24-nor-4-aza-5α-cholane-23-nitrile,   4-methyl-3-oxo-4-aza-5α-pregnane-21-carbonitrile,   24-nor-4-aza-5α-chol-1-ene-23-nitrile,   24-nor-4-aza-cholane-23-nitrile,   4-methyl-24-nor-4-aza-5α-chol-1-ene-23-nitrile,   3-oxo-4-aza-5α-pregn-1-en-21-carbonitrile,   3-oxo -4-aza-5α-pregnane-21-carbonitrile,   4-methyl-3-oxo-4-aza-5α-pregnane-21-nitrile,   4-methyl-3-oxo-4-aza-5α-cholane-24-nitrile,   3-oxo-4-aza-5α-chol-1-ene-24-nitrile,   4-methyl-3-oxo-21-nor-4-aza-5α-cholane-24-nitrile,   3-oxo-21-nor-4-aza-5α-cholane-24-nitrile,   20,20-dimethyl-3-oxo-4-aza-5α-preg-1-ene-21-nitrile, and   3-oxo-4,20,20-trimethyl-4-aza-5α-pregnane-21-nitrile.   
     
     
       8. The compound according to claim 1 wherein: Alk is selected from ethenyl, propenyl, isopropenyl, 1-butenyl, and 2-butenyl.   
     
     
       9. A pharmaceutical composition comprising 0.5 to 1000 mg of the compound of claim 1 in a pharmaceutically acceptable carrier therefor.